tbuckley/cabot-search huggingface dataset:
Efficacy of first-line treatment for chronic lymphocytic leukemia: A Bayesian network meta-analysis.
Authors: Asher Chanan-Khan, Keri Yang, Tom Liu, Aileen Cohen, Kyle Fahrbach, Yunyang Wang, Boxiong Tang
Journal: Journal of Clinical Oncology (2022)

e19526 Background: Zanubrutinib is an oral, highly selective, next-generation Bruton tyrosine kinase inhibitor. Efficacy of zanubrutinib was compared with bendamustine + rituximab (BR) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) in the phase 3 SEQUOIA trial (NCT03336333). However, efficacy of zanubrutinib compared with other frontline CLL treatments remains unknown. The goal of this network meta-analysis of randomized controlled trials (RCTs) was to estimate the relative efficacy of zanubrutinib compared with standard frontline treatments for CLL. Methods: A total of 4 relevant RCTs were identified by a targeted literature review conducted throughout January 2022, CLL11 (NCT01010061), ALLIANCE (NCT01886872), MABLE (NCT01056510), and SEQUOIA. A feasibility assessment was performed to ensure that RCTs included within each population strata did not differ with respect to effect modifiers including presence of mutation, age, del11, and del17 status. A network was constructed for the composed 4 RCTs to compare the efficacy of zanubrutinib with bendamustine + rituximab, chlorambucil + obinutuzumab, chlorambucil + rituximab, and ibrutinib in patients with previously untreated CLL. Bayesian NMA models were conducted to simultaneously synthesize hazard ratio (HR) and 95% credible intervals (CI) for investigator-assessed progression-free survival (PFS). A constant hazard ratio was assumed in the NMA analysis. Statistical analyses were performed using codes suggested by the National Institute for Health and Care Excellence. Results: The efficacy results of the NMA indicated a statistically significant improvement in PFS for zanubrutinib over bendamustine + rituximab (HR=0.42; [95% CI=0.27, 0.65]), chlorambucil + obinutuzumab (0.45 [0.23, 0.86]), and chlorambucil + rituximab (0.22 [0.12, 0.41]). Zanubrutinib achieved comparable PFS to ibrutinib (1.07 [0.59, 1.94]). Conclusions: This is the first NMA to compare the efficacy of zanubrutinib with all commonly utilized first-line treatment for TN CLL. Results from this indirect treatment comparison suggested that the PFS for zanubrutinib may be statistically significantly better than immunochemotherapy. Findings from this study require validation with further large scale RCTs with longer follow up time.[Table: see text]
Remodeling of the m6A RNA landscape in the conversion of acute lymphoblastic leukemia cells to macrophages
Authors: Alberto Bueno-Costa, David Piñeyro, Carlos A. García-Prieto, Vanessa Ortiz-Barahona, Laura Martinez-Verbo, Natalie A. Webster, Byron Andrews, Nitzan Kol, Chen Avrahami, Sharon Moshitch-Moshkovitz, Gideon Rechavi, Manel Esteller
Journal: Leukemia (2022)
NFB-03. Neurological manifestations in children and adolescents with Neurofibromatosis type 1 - Implications for management and surveillance
Authors: Daniela Angelova-Toshkina, Johannes Holzapfel, Stefanie Bette, Josua Decker, Fabio Hellmann, Thomas Traunwieser, Simon Huber, Mareike Schimmel, Kurt Vollert, Brigitte Bison, Thomas Kröncke, Elisabeth André, Dagmar Wieczorek, Astrid K Gnekow, Michael C Frühwald, Michaela Kuhlen
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: We aimed to (1) characterize the spectrum of clinical phenotypes of NF1 in a random pediatric population, (2) correlate genotype with phenotypic expression for those with a genetic diagnosis, and (3) explore radiological features of NF1 in the central nervous system (CNS) by radiomics analyses to predict clinical course. METHODS: We performed a database search in the hospital information system of the University Children′s Hospital between January 2017 and December 2020 for patients with NF1 and evaluated the clinical phenotype by retrospective chart review. RESULTS: 75 children/adolescents were identified with suspicion/clinical diagnosis of NF1 (median age 10.0 years (range, 1.1-22.6); 35 female), confirmatory revised “diagnostic criteria” were met in 57 patients at the last follow-up. Per number of documented items, major signs were detected as 73/75 café-au-lait macules, 31/63 freckling, 38/71 neurofibromas (thereof 21 plexiform neurofibromas), 18/43 optic pathway glioma, 5/66 Lisch nodules, and two patients with sphenoid dysplasia. Genetic analysis (31/75) identified pathogenic NF1 variants in 27 patients. In 20/66 cases a parent met diagnostic criteria. Cognitive symptoms included developmental delay (28/68), learning deficits (12/48), attention-deficit hyperactivity disorder (3/53), and behavior anomalies (7/63). Classical unidentified bright objects were seen in 29/43, other intracranial tumors in 7/43, and cerebrovascular abnormalities in 5/43. Analysis of imaging features of the CNS in these patients will involve lesion segmentation and radiomics features. Symptomatic/progressive low-grade glioma necessitated neurosurgical resection (4/25) and/or chemotherapy (12/25). In 10/25 neuropsychological functions were assessed by the German neuropsychological basic diagnostic instrument. Until June 30th, 2021, one patient died of progressive plexiform neurofibroma. CONCLUSIONS: A wide range of neurological manifestations, including neuropsychological deficits, should raise the suspicion of NF1 in an unselected pediatric population. We expect imaging features of the CNS to better predict the clinical course and enhance decision-making.
HGG-18. Long-term efficacy and safety of larotrectinib in paediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system (CNS) tumours
Authors: Karsten Nysom, François Doz, Birgit Geoerger, Ingrid Øra, Sebastien Perreault, Ricarda Norenberg, Marc Fellous, Esther De La Cuesta, Theodore W Laetsch, Cornelis M van Tilburg
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumours. Larotrectinib, a highly selective TRK inhibitor, demonstrated an objective response rate (ORR) of 75% across 206 evaluable patients with various non-primary CNS cancers (Hong et al, ASCO 2021). We report long-term data on larotrectinib-treated paediatric patients with TRK fusion-positive primary CNS tumours. METHODS: Patients aged &amp;lt;18 years with TRK fusion-positive primary CNS tumours enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Larotrectinib was administered at 100 mg/m2 (maximum: 100 mg) twice-daily. Response was investigator-assessed per RECIST v1.1 and RANO. RESULTS: As of July 2021, 28 patients with TRK fusion-positive primary CNS tumours were enrolled, including 14 high-grade and eight low-grade gliomas. Median age at enrolment was 7.0 years (range 1.0–17.0). Twenty-three patients (82%) received prior systemic therapy and 12 (43%) received prior radiotherapy. The ORR was 39% (95% confidence interval [CI] 22–59): three complete responses, eight partial responses, 15 stable disease and two progressive disease. The 24-week disease control rate was 82% (95% CI 63–94). Median duration of response (DoR) was not reached; median follow-up was 25.6 months. Median progression-free survival was 21.9 months (95% CI 9.2–not estimable). Median overall survival (OS) was not reached; median follow-up was 27.6 months. DoR and OS 24-month rates were 53% and 71%, respectively. Treatment duration ranged from 1.0 to 39.0+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. Grade 3–4 events occurred in three patients (increased gamma-glutamyltransferase, hyperglycaemia, hypernatraemia, hyponatraemia and neutropaenia). No patients discontinued treatment due to TRAEs. Fourteen patients progressed on treatment; four continued treatment post-progression for ≥4 weeks. CONCLUSION: Larotrectinib demonstrated high disease control rate, durable responses and a manageable safety profile. These results support testing for NTRK gene fusions in paediatric patients with primary CNS tumours.
Risk of second primary malignancy in patients with primary myelofibrosis: A SEER database study.
Authors: Utsav Joshi, Adheesh Bhattarai, Suman Gaire, Simrat Gill, Vishakha Agrawal, Uttam Bhetuwal, Peter Kouides, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2022)

e19079 Background: Primary myelofibrosis (PMF) carries a poorer prognosis compared to other BCR-ABL-negative myeloproliferative diseases (MPD), and there is increased risk of early mortality due to blast transformation, thrombosis, bleeding complications, and progression of disease. Prior studies report greater incidence of second primary malignancy (SPM) among MPD patients, although the true risk in PMF has not been elucidated. We performed a large database study to evaluate the risk of SPM in PMF patients and analyzed the effects of sociodemographic factors on the risk of SPM. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify all patients with a histologic diagnosis of PMF from 2009 to 2018. SPM was defined as any subsequent malignancy that developed at least 1 year after the diagnosis of PMF. Using multiple primary standardized incidence ratio (SIR) session of the SEER*Stat software (version 8.3.9), we calculated SIR and absolute excess risk (AER) of SPM for the entire cohort of PMF and also stratified based on age, sex, race, marital status, receipt of chemotherapy, follow-up duration, and year of diagnosis. We generated the 95% confidence intervals (CI) and p-values assuming Poisson distribution of the observed incidences of SPM. Results: A total of 5,273 patients with PMF were included in the analysis, of which 342 patients (6.4%) developed SPM. SPM occurred at SIR of 1.97 (95% CI 1.77-2.18, p&lt;0.05) and AER of 151.87 per 10,000 population. A significantly higher incidence of melanoma (SIR 1.96, 95% CI 1.14-3.14, p&lt;0.05), lymphoma (SIR 3.45, 95% CI 2.31-4.96, p&lt;0.05), and leukemia (SIR 26.87, 95% CI 22.69-31.59, p&lt;0.05) was observed. There was no statistically significant difference in SIR based on sex, race, marital status, follow-up duration, and receipt of chemotherapy. The risk was significantly higher in patients ≤60 years vs patients &gt;60 years (SIR 2.34, 95% CI 1.89-2.86 vs SIR 1.86, 95% CI 1.65-2.10, p 0.01) and for PMF diagnosed after 2009 vs ≤2009 (SIR 2.64, 95% CI 2.26-3.07 vs SIR 1.61, 95% CI 1.40-1.85, p&lt;0.001). Conclusions: Patients with PMF are at a high risk of developing SPM, especially leukemia and lymphoma. Data suggests higher incidence of SPM in patients aged ≤60 years and in the decade after 2009. The impact of ruxolitinib, which was approved in 2011, on the incidence of SPM deserves further study. [Table: see text]
RONC-18 Radiosurgery for Primary and Metastatic CNS Malignancies in the Pediatric Population
Authors: Katherine Chen, David Raleigh, Penny Sneed, Shannon Fogh, Jean Nakamura, Lauren Boreta, Anuradha Banerjee, Sabine Mueller, Kurtis Auguste, Nalin Gupta, Steve Braunstein
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: The purpose of this study is to describe outcomes after pediatric radiosurgery for malignant CNS lesions. METHODS: Retrospective chart review was performed for 31 pediatric patients treated at a single institution with Gamma Knife stereotactic radiosurgery (SRS) for primary or metastatic CNS malignancies between 2000-2020. RESULTS: 25 patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4. 71% of patients had received a prior course of involved-field external beam radiation to the brain to a median dose of 59.4 Gy in 33 fractions. Median age at SRS was 14 years (range 4-21). Radiosurgery was predominantly performed in a single fraction to a median dose of 17 Gy to a total of 42 targets among 29 patients. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger lesions. Median follow up after SRS was 44 months. 7 patients (23%) had no evidence of disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at the site of their treated lesion at a median of 13 months after SRS. 20 patients (65%) developed recurrent disease in the CNS outside of the radiosurgery field at a median of 11 months after SRS. 4 patients developed toxicity from SRS related to radiation treatment effect, all of which occurred within 1 year of SRS. CONCLUSIONS: SRS for malignant CNS lesions in the pediatric population provides effective local control and is well-tolerated. However, there remains a substantial risk of distant CNS failures given the nature of recurrent or metastatic disease in these patients.
MEDB-09. Unraveling the role of unfolded protein response in medulloblastoma cancer stem cells
Authors: Zaira Spinello, Luana Abballe, Elena Splendiani, Angela Di Giannatale, Felice Giangaspero, Angela Mastronuzzi, Elisabetta Ferretti, Evelina Miele, Giuseppina Catanzaro
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor. The current clinical approach consists of multimodal strategies with debilitating long-term effects and risk of tumor recurrence. Medulloblastoma stem cells (MBSCs) are a fraction of tumor cells with high proliferation potential and the capability to adapt to adverse/restrictive conditions in tumor milieu thus driving the refractoriness to conventional therapies. Recently, high basal levels of Unfolded Protein Response (UPR) molecules have been found in tumors of different tissue-origin and are correlated with poor prognosis and low patient survival. However, little is known about the role of UPR in MB. We investigated the expression and activation of UPR players in MBSCs. Human group 3 MB (G3MB) cell lines, specifically CHLA-01, D283- and D341-Med, were grown in Vitamin A and/or FBS or in stem selective medium (B27™) for 72 h before collection. Cells were fixed, stained with proper primary antibodies and images were acquired by confocal microscopy. The analysis of the transcription factors ATF-4 and CHOP revealed their elevated nuclear expression and co-localization, which resulted to be more marked in G3MB stem-like cells than in the differentiated ones. Also the ATF-6 branch was investigated, in differentiating conditions D283 and D341-Med showed a greater activation of ATF-6, represented by its nuclear localization, in respect to stem cells, while CHLA-01 did not show differences. Conversely XBP1, the transcription factor downstream IRE1 signaling, was not expressed in the three cell lines. Lastly, a Kaplan-Meier analysis on MB patients showed a worse prognosis with a shorter survival rate of patients expressing high ATF4 transcript levels. Our results reveal, even in resting conditions, preferential activation of the PERK branch in G3MB cells grown in stem-like condition suggesting that ATF-4 might be a promising therapeutic and prognostic factor to specifically target the stem compartment in aggressive MB.
Race- and sex-based variation in industry research and general payments to medical oncologists in the United States.
Authors: Imraan Jan, Brian De, Young Suk Kwon, Robert Freeman, Kelsey Larkin, Shyamala Subramanian, Prathyusha Pandu, Amy Song, Meredith Young, Mutlay Sayan, Ethan B. Ludmir, Bruce George Haffty, Malcolm David Mattes
Journal: Journal of Clinical Oncology (2022)

11050 Background: Industry partnerships offer financial incentives, prestige, and can facilitate career advancement in oncology. However, not all physicians may have equal access to these opportunities. We hypothesized that physicians who are underrepresented in the medical oncology workforce based on race, ethnicity, and gender receive less industry funding. Methods: All US medical oncologists (MOs) who received ≥1 industry research payment between 2016 and 2020 according to the Open Payments database were included in this retrospective study. Information extracted from Open Payments included MO’s name, institution, research payments (i.e. funding for a research project where the physician is a Principle Investigator), and general payments (i.e. fees not associated with research, such as consulting and travel fees). Additional web searches were conducted using institutional websites, NPPES NPI registry, LinkedIn, Doximity, Scopus, and NIH RePORTER to determine each MO’s race, ethnicity, sex, academic rank, degrees, h-index, institutional NIH research funding rank, and individual receipt of NIH funding. Log-linear regression was performed to identify associations of both industry and general payment data. Results: Of 7,542 physicians meeting inclusion criteria, 69% were male, 65% White, 29% Asian, 2% Black, and 4% Hispanic, which is comparable to the American Medical Association Physician Masterfile figures for MO. The median sum research payment and general payment was $134,857 and $11,537 per physician respectively. Significantly higher mean research payments were associated with an MS (+72%; P = 0.003) or PhD degree (+30%; P = 0.009), h-index (+3%; P &lt; 0.001), top 50 institution rank by NIH funding (+44%; P &lt; 0.001), and associate professor rank (+95%; P &lt; 0.001). Significantly lower mean research payment were observed for Black physicians (-36%; P = 0.022) and those with non-academic affiliation (-47%; P &lt; 0.001). No significant association was observed between sex and research payment. Significantly higher mean general payments were associated with male sex (+46%; P &lt; 0.001), MS degree (+171%; P &lt; 0.001), h-index (+2%; P &lt; 0.001), and Asian race (+72%; P &lt; 0.001). Significantly lower mean general payments were associated with an affiliation with a non-academic practice (-31%; P = 0.012). Conclusions: Black physicians received smaller sums of industry research payments compared to White physicians. Female sex was associated with decreased general payments compared to male sex. Further exploring the underlying mechanisms determining access to industry payments may help facilitate greater equity and inclusivity in oncology.
Detection of individualized mutation using plasma and urinary circulating tumor DNA in patients with upper tract urothelial carcinoma
Authors: D. Tamura, M. Abe, R. Kato, Y. Kato, S. Maekawa, M. Kanehira, R. Takata, Y. Suzuki, H. Nakagawa, S. Nishizuka, O. Wataru
Journal: European Urology (2022)
The cultural learning account of first impressions
Authors: Richard Cook, Adam Eggleston, Harriet Over
Journal: Trends in Cognitive Sciences (2022)

Humans spontaneously attribute character traits to strangers based on their facial appearance. Although these 'first impressions' typically have no basis in reality, some authors have assumed that they have an innate origin. By contrast, the Trait Inference Mapping (TIM) account proposes that first impressions are products of culturally acquired associative mappings that allow activation to spread from representations of facial appearance to representations of trait profiles. According to TIM, cultural instruments, including propaganda, illustrated storybooks, art and iconography, ritual, film, and TV, expose many individuals within a community to common sources of correlated face-trait experience, yielding first impressions that are shared by many, but typically inaccurate. Here, we review emerging empirical findings, many of which accord with TIM, and argue that future work must distinguish first impressions based on invariant facial features (e.g., shape) from those based on facial behaviours (e.g., expressions).
Crosstalk among T-cell CX3CR1, immune checkpoints and toll-like receptor 4 signaling pathway in BCG-unresponsive nonmuscle invasive bladder cancer: Mechanism of action of OncoTherad Nano-Immunotherapy.
Authors: João Carlos Cardoso Alonso, Bianca Ribeiro de Souza, Giovana Leme, Ianny Brum Reis, Juliana Mattoso Gonçalves, Adriano Angelo Cintra, Leandro Luiz Lopes de Freitas, Fabio Gomes Pereira, Athanase Billis, Wagner José Fávaro
Journal: Journal of Clinical Oncology (2022)

e16551 Background: This study detailed and characterized the mechanisms of action of OncoTherad nano-immunotherapy based on modulation of Toll-like Receptor 4 (TLR4) signaling pathway, CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation) and immune checkpoints in patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-grade non-muscle invasive bladder cancer. Methods: A single-center open-label (Paulinia Municipal Hospital, Brazil) and single-arm phase 1/2 study (Clinical Trial: RBR-6swqd2) was applied in 44 patients (30 male and 14 female) with BCG-unresponsive NMIBC (≥ 1 prior course of BCG therapy) submitted to OncoTherad immunotherapy for 24 months. Patient follow-ups were performed with systematic mapping biopsies of the bladder every 3 months for the first year and every 6 months thereafter for up to 2 years. Bladder biopsies of each patient (n = 44) were divided into 2 groups: Group 1 (initial biopsy, before OncoTherad treatment); and Group 2 (bladder biopsy after OncoTherad treatment). Subsequently, the samples were submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3), CX3CR1 + CD8 + T-cells, immune checkpoints (PD-1/PD-L1 CTLA-4) and Regulatory T cells (FOXP3). Results: After 24-months follow-up, pathological complete response rate was 72.7% (95% CI) and recurrence-free survival of 21.4 months. Bladder samples from patients submitted to OncoTherad treatment (Group 2) showed intensified TLR4, TRIF, TBK1, IRF-3 and IFN-γ immunoreactivities when compared (p &lt; 0.01) to initial biopsies (Group 1). Furthermore, as result of interferon signaling pathway (TRIF-dependent pathway) induction by OncoTherad, intensified CX3CR1 immunoreactivities (p &lt; 0.01) were found in the Group 2. In contrast, PD-1/PD-L1 immunoreactivities were decreased (p &lt; 0.01) in the Group 2 when compared to Group 1. No statistical differences were found between the two groups for FOXP3 and CTLA4. Conclusions: OncoTherad nano-immunotherapy led to activation of TLR4-mediated innate immune system, resulting in increased interferon signaling pathway, which was fundamental in the activation of antitumor CD8 + T-cells and decrease of PD-1/PD-L1 expression in the bladder microenvironment. These important findings are relevant concerning the treatment of patients with NMIBC presenting high-risk of progression that are BCG-unresponsive.